title: Clinical whole-exome sequencing for the diagnosis of mendelian disorders.
abstract: BACKGROUND
  Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders.
  
  
  METHODS
  We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients.
  
  
  RESULTS
  We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic phenotypes. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had autosomal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders.
  
  
  CONCLUSIONS
  Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.).
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Reid
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Bainbridge
authors.forename: Alecia
authors.initials: A
authors.lastname: Willis
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Ward
authors.forename: Alicia
authors.initials: A
authors.lastname: Braxton
authors.forename: Joke
authors.initials: J
authors.lastname: Beuten
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.forename: Zhiyv
authors.initials: Z
authors.lastname: Niu
authors.forename: Matthew
authors.initials: M
authors.lastname: Hardison
authors.forename: Richard
authors.initials: R
authors.lastname: Person
authors.forename: Mir Reza
authors.initials: MR
authors.lastname: Bekheirnia
authors.forename: Magalie S
authors.initials: MS
authors.lastname: Leduc
authors.forename: Amelia
authors.initials: A
authors.lastname: Kirby
authors.forename: Peter
authors.initials: P
authors.lastname: Pham
authors.forename: Jennifer
authors.initials: J
authors.lastname: Scull
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005799:Genes, Dominant; D005808:Genes, Recessive; D050172:Genes, X-Linked; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D009154:Mutation; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult